Stearoyl-CoA desaturase (SCD) catalyzes the committed step in the biosynthesis of monounsaturated fatty acids from saturated fatty acids. This reaction involves the introduction of a cis-double bond in the Δ-9 position (between carbons 9 and 10) in a spectrum of methylene-interrupted fatty acyl-CoAs. The roles of monounsaturated fatty acids are diverse and crucial in living organisms. Palmitoleic and oleic acids are the major monounsaturated fatty acids in membrane phospholipids, triglycerides, and cholesterol esters (Miyazaki, M. et al. (2000) J. Biol. Chem. 275, 30132-30138). A proper ratio of saturated to monounsaturated fatty acids contributes to membrane fluidity, whereas changes in cholesterol esters and triglyceride levels affect lipoprotein and lipid metabolism (Miyazaki, M. et al. (2000) J. Biol. Chem. 275, 30132-30138; Feng, B. and Tabas, I. (2002) J. Biol. Chem. 277, 43271-43280; and Cohen, P. et al. (2002) Science 297, 240-243). Apart from being components of lipids, monounsaturated fatty acids have also been implicated as mediators in signal transduction and differentiation of neurons and other cells (Garbay, B. et al. (1998) J. Neurochem. 71, 1719-1726). Monounsaturated fatty acids have also been shown to regulate food intake in the brain (Obici, S. et al. (2002) Diabetes 51, 271-275). Given the multiple roles of monounsaturated fatty acids, alterations in SCD activity in mammals would be expected to have potent effects on lipid metabolism and to play a role in the propensity to develop obesity, atherosclerosis, and metabolic diseases (Miyazaki, M. and Ntambi, J. M. (2003) Prostaglandins Leukotrienes Essent. Fatty Acids 68, 113-121; and Ntambi, J. M. (1999) J. Lipid Res. 40, 1549-1558).
A number of mammalian SCD genes have been cloned and studied. Two SCD genes have been cloned in rats and three well characterized SCD genes (mSCD1, mSCD2, and mSCD3) have been cloned in mice (Ntambi, J. M. et al. (1988) J. Biol. Chem. 263, 17291-17300; Kaestner, K. H. et al. (1989) J. Biol. Chem. 264, 14755-14761; Zheng, Y. et al. (2001) Genomics 71, 182-191, all of which are herein incorporated by reference in their entirety). In addition, two human SCD genes, hSCD1 and hSCD5, have been cloned (Zhang, L. et al. (1999) Biochem. J. 340, 255-264; and Beiraghi, S. et al. (2003) Gene 309, 11-21). Human SCD1 is highly homologous to the mouse and rat SCDs.
It has been recently demonstrated that the regulation of SCD1 by leptin plays a crucial role in signaling the body to either store fat or burn it. Obese mice, which lack leptin, lost weight because of increased energy expenditure when genetically crossed with a strain of mice carrying a mutation in SCD1 (Cohen, P. et al. (2002) Science 297, 240-243). The missing SCD1 enzyme also corrected a major clinical problem called fatty liver, which is found in obese mice and humans. Leptin has also been found to reduce fat deposition in other tissues such as muscle and heart (Minokoshi, Y. et al. (2002) Nature 415, 339-343; Atkinson, L. L. et al. (2002) J. Biol. Chem. 277, 29424-29430; Zhou, Y. T. et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 1784-1789; and Unger, R. H. (2002) Annu. Rev. Med 53, 319-336).
The expression of different SCD isoforms varies among tissues. For example, mSCD1 is the main isoform expressed in the liver whereas mSCD2 is constitutively expressed in the brain (Ntambi, J. M. et al. (1988) J. Biol. Chem. 263, 17291-17300; and Kaestner, K. H. et al. (1989) J. Biol. Chem. 264, 14755-14761). In tissues such as the adipose and eyelids, both mSCD1 and mSCD2 are expressed. On the other hand, all three mouse isoforms are expressed in skin, Harderian, and preputial glands (Zheng, Y. et al. (2001) Genomics 71, 182-191; and Miyazaki, M. et al. (2001) J. Biol. Chem. 276, 39455-39461). The reason for having two or more SCD isoforms in the same tissue seems to be related to substrate specificity of the isomers and their regulation through tissue-specific transcription factors (Miyazaki, M. et al. (2001) J. Nutr. 131, 2260-2268).
It is of great interest in the art to identify other isoforms of SCD, if they exist, so that the expression pattern and regulation of all SCD isoforms can be studied and compared and their connection to various diseases and conditions be assessed. The identification of new SCD isoforms will further assist, among other things, the development of target-specific drugs, i.e., drugs that inhibit the activity of a disease-causing isoform but not other isoforms that perform important normal, physiological functions.